Publication

• Title: Effect of a Low vs Intermediate Tidal Volume Strategy on Ventilator-Free Days in Intensive Care Unit Patients Without ARDS: A Randomized Clinical Trial
• Acronym: PReVENT
• Year: 2018
• Journal published in: JAMA
• Citation: Simonis FD, Serpa Neto A, Binnekade JM, Braber A, Bruin KCM, Determann RM, et al; Writing Group for the PReVENT Investigators. Effect of a low vs intermediate tidal volume strategy on ventilator-free days in intensive care unit patients without ARDS: a randomized clinical trial. JAMA. 2018;320(18):1872-1880.

Context & Rationale

• Background

  • Low tidal volume ventilation improves outcomes in ARDS, and ventilator-induced lung injury is biologically plausible even in “non-ARDS” lungs.
  • Before PReVENT, evidence supporting low tidal volumes in patients without ARDS was dominated by observational studies and meta-analyses with important heterogeneity and confounding risk.
  • Routine adoption of very low tidal volumes in non-ARDS patients carried potential trade-offs (hypercapnia/respiratory acidosis, dyssynchrony, and possible downstream sedation escalation).
• Research Question/Hypothesis

  • Whether a low tidal volume strategy (target 4–6 mL/kg predicted body weight) increases ventilator-free days at day 28 compared with an intermediate tidal volume strategy (target 8–10 mL/kg predicted body weight) in invasively ventilated ICU patients without ARDS.
• Why This Matters

  • Patients without ARDS comprise the majority of invasively ventilated ICU patients, so even small differences could have major population impact.
  • A negative (or neutral) RCT is clinically meaningful if it prevents unnecessary “ultra-protective” practices that add physiologic burdens without benefit.
  • Clarifies whether ARDS-derived lung-protective targets should be applied universally versus tailored to lung mechanics and illness trajectory.

Design & Methods

• Research Question: In adult ICU patients invasively ventilated without ARDS and expected to require ventilation >24 hours, does a low tidal volume strategy increase ventilator-free days to day 28 versus an intermediate tidal volume strategy?
• Study Type: Investigator-initiated, multicentre, randomised, parallel-group, open-label clinical trial in 6 ICUs in the Netherlands; stratified by centre and location of intubation (in ICU vs outside ICU).
• Population:
  • Setting: ICU; randomisation required within 1 hour after start of invasive ventilation in the ICU.
  • Inclusion: adults receiving invasive ventilation; no ARDS at initiation; expected duration of ventilation >24 hours.
  • Key exclusions: ARDS; age <18 years; pregnancy; invasive ventilation >12 hours before ICU admission; history of pulmonary disease (e.g., severe COPD or pulmonary fibrosis); uncontrolled intracranial pressure; new pulmonary thromboembolism; previous enrolment in the trial.
• Intervention:
  • Low tidal volume strategy targeting 4–6 mL/kg predicted body weight.
  • Volume-controlled ventilation: started at 6 mL/kg; decreased by 1 mL/kg each hour to a minimum of 4 mL/kg.
  • Pressure support ventilation: lowest support achieving target; minimum pressure support 5 cm H₂O; if tidal volume remained >8 mL/kg at minimum support, this was accepted.
  • Protocolised adjustments permitted for dyspnoea/distress (tidal volume could be increased in 1 mL/kg steps if needed).
  • Additional analgosedation or muscle relaxants specifically to enable delivery of the assigned strategy was not permitted.
• Comparison:
  • Intermediate tidal volume strategy targeting 8–10 mL/kg predicted body weight (initially 10 mL/kg in volume-controlled ventilation).
  • Volume-controlled ventilation: started at 10 mL/kg; if plateau pressure exceeded 25 cm H₂O, tidal volume was reduced to keep plateau pressure ≤25 cm H₂O.
  • Pressure support ventilation: support adjusted to target tidal volume while maximum airway pressure remained <25 cm H₂O.
  • Other ventilator settings (e.g., PEEP, FiO₂) and weaning practices followed local ICU guidance with protocolised daily assessment.
• Blinding: Unblinded (ventilator settings not concealable); outcomes were collected without blinding, raising theoretical risk of performance bias for decisions affecting ventilation duration (mitigated by protocolised weaning/extubation criteria).
• Statistics: A total of 952 patients (476/group) were required to detect a 1-day difference in ventilator-free days at day 28 (assumed SD 5), with 80% power at a 5% significance level and allowing 20% dropout; primary analysis was intention-to-treat with a t test for the between-group difference (sensitivity analyses included a mixed model incorporating stratification factors).¹
• Follow-Up Period: Primary outcome assessed through day 28; mortality assessed through day 90; ICU and hospital length of stay assessed until discharge.

Key Results

This trial was not stopped early. No interim analyses were performed; recruitment and follow-up were completed as planned.

Outcome	Low tidal volume	Intermediate tidal volume	Effect	p value / 95% CI	Notes
Ventilator-free days to day 28, mean (SD)	21.0 (9.3) (n=475)	21.0 (9.0) (n=480)	Mean difference −0.27 days	95% CI −1.74 to 1.19; P=0.71	Primary outcome
Duration of ventilation among survivors to day 28, median (IQR)	3.3 (2.0–4.9) (n=414)	3.3 (2.0–4.9) (n=425)	Mean difference −0.05 days	95% CI −0.77 to 0.67; P=0.90	Secondary outcome
ICU length of stay among survivors, median (IQR)	5.2 (3.5–8.9) (n=415)	5.0 (3.6–9.2) (n=423)	Mean difference −0.01 days	95% CI −0.89 to 0.86; P=0.97	Secondary outcome
Hospital length of stay among survivors, median (IQR)	16.5 (10.9–27.0) (n=415)	16.0 (11.0–25.4) (n=423)	Mean difference 0.31 days	95% CI −1.90 to 2.52; P=0.78	Secondary outcome
Mortality at day 28	61/475 (12.8%)	55/480 (11.5%)	HR 1.12	95% CI 0.90 to 1.40; P=0.30	Time-to-event analysis
Mortality at day 90	93/475 (19.6%)	82/480 (17.1%)	HR 1.08	95% CI 0.90 to 1.29; P=0.45	Time-to-event analysis
ARDS	18/475 (3.8%)	24/480 (5.0%)	RR 0.86	95% CI 0.59 to 1.24; P=0.38	Pulmonary complication
Pneumonia	25/475 (5.3%)	25/480 (5.2%)	RR 0.95	95% CI 0.78 to 1.15; P=0.72	Pulmonary complication
Severe respiratory acidosis (pH <7.25)	82/460 (17.8%)	48/466 (10.3%)	RR 1.54	95% CI 1.20 to 1.98; P=0.001	Adverse event (physiologic harm signal)
Rescue therapy for hypercapnia	9/475 (1.9%)	1/480 (0.2%)	RR 7.70	95% CI 1.01 to 58.67; P=0.02	Low strategy triggered more rescue interventions
Rescue therapy for severe respiratory acidosis	23/475 (4.8%)	7/480 (1.5%)	RR 2.89	95% CI 1.37 to 6.09; P=0.02	Low strategy triggered more rescue interventions
Delirium	206/475 (43.4%)	176/480 (36.6%)	RR 1.15	95% CI 0.99 to 1.34; P=0.06	Borderline (not statistically significant)

• Primary outcome was neutral: ventilator-free days were identical (21.0 vs 21.0) with mean difference −0.27 days (95% CI −1.74 to 1.19; P=0.71).
• Low tidal volume strategy increased clinically relevant hypercapnia-related harms: severe respiratory acidosis occurred more often (17.8% vs 10.3%; RR 1.54; 95% CI 1.20 to 1.98; P=0.001) and prompted more rescue therapies (hypercapnia: RR 7.70; P=0.02; severe respiratory acidosis: RR 2.89; P=0.02).
• Pre-specified subgroup by location of intubation showed effect modification for the primary outcome: in-ICU initiation mean difference in ventilator-free days −2.50 (95% CI −4.63 to −0.36; P=0.02) vs out-of-ICU initiation 1.45 (95% CI −0.52 to 3.43; P=0.15); P for interaction 0.01.

Internal Validity

• Randomisation and Allocation:
  • Allocation used a web-based randomisation system with variable block sizes (2–6), stratified by centre and location of intubation (in ICU vs outside ICU).
  • Post-randomisation blinding was not feasible due to visible ventilator settings.
• Drop out or exclusions:
  • Randomised: 961 patients (477 low tidal volume; 484 intermediate tidal volume).
  • Follow-up was incomplete for 6 patients (2 vs 4), yielding primary outcome data for 955 (475 vs 480).
  • Attrition was minimal and unlikely to bias estimates materially.
• Performance/Detection Bias:
  • Open-label design could influence discretionary decisions that affect ventilator-free days (e.g., timing of weaning/extubation, tracheostomy).
  • Weaning and extubation criteria were protocolised, and mortality endpoints were objective.
• Protocol Adherence:
  • Clear separation in delivered tidal volume early after randomisation, with gradual convergence by day 3 as patients transitioned and targets were adjusted clinically.
  • Additional analgosedation or neuromuscular blockade specifically to permit protocol delivery was not permitted (reducing risk of “protocol-induced” sedation differences).
• Baseline Characteristics:
  • Groups were broadly comparable at baseline (e.g., SAPS II median 52 vs 51; PaO₂/FiO₂ 197 vs 198; baseline tidal volume 7.0 vs 7.3 mL/kg predicted body weight).
  • Most patients were intubated outside the ICU (72.1% vs 70.3%), and median time from start of ventilation to randomisation was 0.88 hours (IQR 0.36–2.01).
• Heterogeneity:
  • Broad “non-ARDS” population with mixed indications for ventilation (including high proportions of coma/cardiac arrest), increasing clinical heterogeneity and potentially diluting a small true effect.
  • Pre-specified subgroup testing suggested heterogeneity by location of intubation, but this finding is vulnerable to multiplicity and contextual confounding.
• Timing:
  • Early randomisation relative to ICU ventilation start (median 0.57 hours from ICU admission to randomisation; IQR 0.23–1.00) supports causal attribution to early ventilator strategy.
  • A substantial proportion of eligible patients were not enrolled due to logistical constraints (e.g., missed enrolment; inability to randomise within 1 hour), introducing potential selection effects.
• Dose:
  • “Low” strategy targeted 4–6 mL/kg predicted body weight; “intermediate” strategy targeted 8–10 mL/kg predicted body weight, with pressure/plateau limits applied in the intermediate group.
  • The intermediate strategy is not equivalent to the historical “traditional” 12 mL/kg comparator used in early ARDS trials; this narrows contrast and may reduce detectable benefit.
• Separation of the Variable of Interest:
  • Delivered tidal volume (after titration), median (IQR): 5.9 (5.2–6.7) vs 9.1 (7.9–10.0) mL/kg predicted body weight.
  • Delivered tidal volume day 1, median (IQR): 5.9 (5.3–6.8) vs 9.0 (8.0–10.0) mL/kg predicted body weight.
  • Delivered tidal volume day 2, median (IQR): 6.6 (5.6–7.6) vs 9.0 (7.9–10.0) mL/kg predicted body weight.
  • Delivered tidal volume day 3, median (IQR): 7.3 (5.9–8.0) vs 9.1 (7.9–10.1) mL/kg predicted body weight.
  • From randomisation to day 3, tidal volume (mL/kg predicted body weight), median (IQR): 6.2 (5.6–7.4) vs 8.3 (7.6–9.1); mean difference −2.16 (95% CI −2.25 to −2.07); P<0.001.
  • From randomisation to day 3, driving pressure (cm H₂O), median (IQR): 12 (10–15) vs 13 (11–16); mean difference −1.23 (95% CI −1.58 to −0.87); P<0.001.
• Key Delivery Aspects:
  • Ventilator settings were checked at least every 8 hours, supporting implementation fidelity.
  • Short median ventilation duration (~3.3 days among survivors) limits exposure time and may reduce the likelihood of detecting delayed prevention effects (e.g., incident ARDS).
• Outcome Assessment:
  • Ventilator-free days combine death and ventilation duration, capturing a patient-centred and resource-relevant endpoint.
  • Because ventilator-free days incorporate clinician-mediated processes (weaning/extubation), open-label design remains a residual risk for bias despite protocolised criteria.
• Statistical Rigor:
  • Planned sample size was achieved (961 randomised vs 952 required) with prespecified analysis methods.
  • No interim analyses were performed, reducing risk of early-stopping bias.
  • Multiple secondary endpoints were analysed without multiplicity adjustment, so borderline findings should be interpreted cautiously.

Conclusion on Internal Validity: Overall, internal validity appears moderate-to-strong given robust randomisation, minimal attrition, and clear early treatment separation; the main threats are the open-label design (process-mediated primary endpoint) and the narrowing separation over time in a relatively short-duration ventilation population.

External Validity

• Population Representativeness:
  • Conducted in 6 Dutch ICUs; patients were predominantly older adults with mixed indications for intubation (notably coma/cardiac arrest).
  • Key exclusions (e.g., chronic pulmonary disease, prolonged pre-ICU ventilation >12 hours, uncontrolled intracranial hypertension) limit direct applicability to common ICU subgroups such as severe COPD.
• Applicability:
  • Most applicable to high-resource ICUs with frequent ventilator reassessment and early transition to assisted modes.
  • Does not address outcomes when “usual care” involves very high tidal volumes (e.g., ≥12 mL/kg predicted body weight), because the comparator strategy was intermediate and included pressure limits.
  • Generalisability to resource-limited settings may be constrained by staffing ratios and the ability to implement frequent titration and protocolised weaning.

Conclusion on External Validity: Overall, external validity is moderate: findings generalise well to similar adult ICU populations without ARDS in comparable systems, but applicability is limited in patients with chronic lung disease, prolonged pre-ICU ventilation, or settings where ventilation practices differ substantially from the intermediate “pressure-limited” comparator.

Strengths & Limitations

• Strengths:
  • Large, pragmatic multicentre RCT in a common ICU population (patients without ARDS).
  • Early enrolment (median <1 hour from initiation of ventilation) enhances causal attribution for early ventilator strategy effects.
  • Clear early physiologic separation (tidal volume, plateau pressure, driving pressure) between groups.
  • Clinically relevant primary endpoint (ventilator-free days) with near-complete follow-up.
• Limitations:
  • Open-label intervention with a process-dependent primary endpoint susceptible to performance bias.
  • Comparator was an intermediate, pressure-limited strategy; contrast with “traditional” high tidal volumes was limited.
  • Treatment separation narrowed by day 3 (median 7.3 vs 9.1 mL/kg predicted body weight), potentially diluting any effect of sustained low tidal volume exposure.
  • Many eligible patients were not enrolled for logistical reasons, creating potential selection effects.
  • Secondary outcomes and subgroup analyses were not adjusted for multiplicity; borderline signals require cautious interpretation.

Interpretation & Why It Matters

• Clinical practice

  • For ICU patients without ARDS, targeting very low tidal volumes (4–6 mL/kg predicted body weight) did not improve ventilator-free days or mortality versus an intermediate, pressure-limited approach, but increased severe respiratory acidosis and use of rescue therapies.
• Physiology and harms

  • Low tidal volumes were “paid for” by higher respiratory rates and a higher burden of hypercapnia/acidosis, without translating into fewer pulmonary complications or shorter ventilation duration.
• Trial design implications

  • In non-ARDS populations with short ventilation exposure and evolving assisted ventilation, achieving and maintaining meaningful dose separation is challenging and may determine whether prevention benefits can be detected.

Controversies & Subsequent Evidence

• Pre-trial evidence from meta-analyses and individual patient data suggested lower tidal volumes might improve outcomes in patients ventilated without ARDS; PReVENT’s neutral clinical findings challenged the assumption that “lower is always better” when the comparator is already a pressure-limited, intermediate tidal volume strategy.⁵⁶⁷
• The accompanying editorial framed PReVENT as a cautionary example for translating ARDS-derived physiological principles into non-ARDS trial design, emphasising heterogeneity of “at-risk” populations, endpoint selection, and the importance of treatment separation over time.²
• Correspondence highlighted interpretive tension between physiologic separation (lower plateau/driving pressures) and lack of clinical benefit, alongside concerns about enrolment constraints and potential dilution due to evolving ventilator modes; the trialists’ reply emphasised adherence to the pragmatic ICU context and the harms observed with the low tidal volume strategy (notably severe respiratory acidosis).³⁴
• A related RCT in ICU patients without ARDS (RELAx) comparing lower versus higher PEEP strategies also found no improvement in ventilator-free days, reinforcing that extrapolating “more protective” ventilator settings beyond ARDS requires empirical confirmation and careful attention to competing harms.⁸
• Contemporary international guidance commonly continues to recommend lung-protective tidal volumes (often ≤8 mL/kg predicted body weight) as a default approach in critically ill mechanically ventilated adults, but PReVENT supports avoiding routine escalation to very low tidal volumes (4–6 mL/kg predicted body weight) in non-ARDS patients when it produces hypercapnic harm without clear benefit.⁹

Summary

• In 961 ICU patients without ARDS, a low tidal volume strategy (target 4–6 mL/kg predicted body weight) did not improve ventilator-free days at day 28 versus an intermediate strategy (target 8–10 mL/kg predicted body weight).
• Mortality at day 28 (12.8% vs 11.5%) and day 90 (19.6% vs 17.1%) did not differ statistically between groups.
• Low tidal volumes produced more severe respiratory acidosis (17.8% vs 10.3%; RR 1.54) and more rescue therapy use for hypercapnia/acidosis.
• Treatment separation was substantial early but narrowed by day 3 (median 7.3 vs 9.1 mL/kg predicted body weight), which may have diluted any benefit of sustained low tidal volume exposure.
• A pre-specified subgroup suggested fewer ventilator-free days with low tidal volumes among patients intubated in the ICU, but this requires cautious interpretation.

Further Reading

Other Trials

• 2000Acute Respiratory Distress Syndrome Network, Brower RG, Matthay MA, et al. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med. 2000;342(18):1301-1308.
• 2010Determann RM, Royakkers A, Wolthuis EK, et al. Ventilation with lower tidal volumes as compared with conventional tidal volumes for patients without acute lung injury: a preventive randomized controlled trial. Crit Care. 2010;14(1):R1.
• 2018Simonis FD, Serpa Neto A, Binnekade JM, Braber A, Bruin KCM, Determann RM, et al; Writing Group for the PReVENT Investigators. Effect of a low vs intermediate tidal volume strategy on ventilator-free days in intensive care unit patients without ARDS: a randomized clinical trial. JAMA. 2018;320(18):1872-1880.
• 2020Writing Committee and Steering Committee for the RELAx Collaborative Group. Effect of a lower vs higher positive end-expiratory pressure strategy on ventilator-free days in intensive care unit patients without acute respiratory distress syndrome: a randomized clinical trial. JAMA. 2020;324(24):2509-2520.
• 2013Futier E, Constantin JM, Paugam-Burtz C, et al; IMPROVE Study Group. A trial of intraoperative low-tidal-volume ventilation in abdominal surgery. N Engl J Med. 2013;369(5):428-437.

Systematic Review & Meta Analysis

• 2012Serpa Neto A, Cardoso SO, Manetta JA, et al. Association between use of lung-protective ventilation with lower tidal volumes and clinical outcomes among patients without acute respiratory distress syndrome: a meta-analysis. JAMA. 2012;308(16):1651-1659.
• 2014Serpa Neto A, Simonis FD, Barbas CSV, et al. Associations between tidal volume size, duration of ventilation, and sedation needs in patients without acute respiratory distress syndrome: an individual patient data meta-analysis. Intensive Care Med. 2014;40(7):950-957.
• 2015Neto AS, Simonis FD, Barbas CSV, et al. Lung-protective ventilation with lower tidal volumes and higher positive end-expiratory pressure is associated with higher survival in patients without acute respiratory distress syndrome: a systematic review and individual patient data analysis. Crit Care Med. 2015;43(10):2155-2163.
• 2015Amato MBP, Meade MO, Slutsky AS, et al. Driving pressure and survival in the acute respiratory distress syndrome. N Engl J Med. 2015;372(8):747-755.

Observational Studies

• 2016Neto AS, Barbas CSV, Simonis FD, et al; PROVE Network Investigators. Epidemiological study on invasive ventilation settings in patients at risk of ARDS: the PRoVENT study. Lancet Respir Med. 2016;4(11):882-893.
• 2014Needham DM, Yang T, Dinglas VD, et al. Timing of low tidal volume ventilation and intensive care unit mortality in acute respiratory distress syndrome: a prospective cohort study. Am J Respir Crit Care Med. 2014;191(2):177-185.
• 2016Bellani G, Laffey JG, Pham T, et al; LUNG SAFE Investigators; ESICM Trials Group. Epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in 50 countries. JAMA. 2016;315(8):788-800.
• 2016Bourdeaux CP, Thomas MJ, Gould TH, et al. Increasing compliance with low tidal volume ventilation in the ICU: a quality improvement initiative. BMJ Open. 2016;6(9):e010129.
• 2001Ely EW, Gautam S, Margolin R, et al. The impact of delirium in the intensive care unit on hospital length of stay. Intensive Care Med. 2001;27(12):1892-1900.

Guidelines

• 2019Griffiths MJD, McAuley DF, Perkins GD, et al. Guidelines on the management of acute respiratory distress syndrome. BMJ Open Respir Res. 2019;6(1):e000420.
• 2021Evans L, Rhodes A, Alhazzani W, et al. Surviving Sepsis Campaign: international guidelines for management of sepsis and septic shock 2021. Intensive Care Med. 2021;47(11):1181-1247.
• 2022Tasaka S, et al. The Japanese clinical practice guidelines for management of ARDS. J Intensive Care. 2022;10(1):32.
• 2024Goodfellow L, Miller AG, Varekojis SM, LaVita CJ, et al. AARC Clinical Practice Guideline: patient-ventilator assessment and management. Respir Care. 2024;69(8):1042-1054.

Overall Takeaway

PReVENT provides high-quality evidence that, in ICU patients ventilated without ARDS, routinely targeting very low tidal volumes (4–6 mL/kg predicted body weight) does not improve ventilator-free days compared with an intermediate, pressure-limited strategy, and increases clinically meaningful hypercapnic harm. The trial is “landmark” because it directly challenges universal adoption of ultra-low tidal volumes outside ARDS and refocuses practice on balancing lung protection against physiologic costs in heterogeneous non-ARDS populations.

Bibliography

• 1Simonis FD, Serpa Neto A, Binnekade JM, et al. Ventilation with lower tidal volumes in patients without acute respiratory distress syndrome: a randomised controlled trial. Trials. 2015;16:197.
• 2Rubenfeld GD, Shankar-Hari M. Lessons from ARDS for non-ARDS research: remembrance of trials past. JAMA. Published online October 24, 2018.
• 3Slagt C, van Eijk L. Tidal volume ventilation strategy in ICU patients without ARDS. JAMA. 2019;321(13):1311-1312.
• 4Serpa Neto A, Simonis FD, Schultz MJ. Tidal volume ventilation strategy in ICU patients without ARDS—Reply. JAMA. 2019;321(13):1312-1313.
• 5Serpa Neto A, Cardoso SO, Manetta JA, et al. Association between use of lung-protective ventilation with lower tidal volumes and clinical outcomes among patients without acute respiratory distress syndrome: a meta-analysis. JAMA. 2012;308(16):1651-1659.
• 6Serpa Neto A, Simonis FD, Barbas CSV, et al. Associations between tidal volume size, duration of ventilation, and sedation needs in patients without acute respiratory distress syndrome: an individual patient data meta-analysis. Intensive Care Med. 2014;40(7):950-957.
• 7Neto AS, Simonis FD, Barbas CSV, et al. Lung-protective ventilation with lower tidal volumes and higher positive end-expiratory pressure is associated with higher survival in patients without acute respiratory distress syndrome: a systematic review and individual patient data analysis. Crit Care Med. 2015;43(10):2155-2163.
• 8Writing Committee and Steering Committee for the RELAx Collaborative Group. Effect of a lower vs higher positive end-expiratory pressure strategy on ventilator-free days in intensive care unit patients without acute respiratory distress syndrome: a randomized clinical trial. JAMA. 2020;324(24):2509-2520.
• 9Evans L, Rhodes A, Alhazzani W, et al. Surviving Sepsis Campaign: international guidelines for management of sepsis and septic shock 2021. Intensive Care Med. 2021;47(11):1181-1247.